In the hippocampus, and other brain areas, plasticity of a synapse allows it to change the way it responds based on its past history of activation, a form of cellular memory. The dynamic nature of a synapse makes it possible to alter episodic and spatial memory formation by persistently increasing responsiveness of synapses, in long-term potentiation (LTP), or decreasing their strength, in long-term depression (LTD). When memories form, particular patterns of neuronal excitation produce long-term changes in synaptic strengths, patterns that, when reactivated, are recalled as memories. At the cellular level, induction of LTP/LTD involve activation of multiple subtypes of glutamate receptors that mediate or regulate local neuronal influx/release of calcium and other second messengers. The N-Methyl-D-aspartic acid receptor (NMDAR) is crucial for the induction of presynaptic and postsynaptic forms of both LTP and LTD, while presynaptic group II metabotropic glutamate receptors (mGluRIIs) contribute to induction of LTD of transmitter release. Presynaptic components of NMDAR-LTD and LTP alter probability of neurotransmitter release, an effect believed to be associated with release of a retrograde signal from the postsynaptic neuron. Both NMDAR and mGluRII activate completely different pathways that each result in LTD of release or the two are mediated by a final common pathway. During vesicular fusion, SNARE proteins work together to mediate vesicular neurotransmitter release. I hypothesize that G?, liberated by mGluRII activation in the presynaptic terminal, binds the C-terminus of the synaptosomal associated protein 25kD (SNAP-25), and that this combines with NMDAR-activated release of the retrograde messenger nitric oxide to evoke LTD. Our laboratory discovered that botulinum toxin A, which cleaves 9 amino acids from the C-terminus of SNAP-25, and presynaptic infusion of the C-terminus of SNAP- 25, each occlude the expression of presynaptic LTD. By measuring the magnitude of LTD, using field and whole cell electrophysiology recording techniques in brain slices, and evaluating the sensitivity of LTD to NMDAR and mGluRII antagonists, I plan to elucidate how each receptor contributes to induction and expression of presynaptic LTD. Using NMDAR and mGluRII antagonists in brain slices from transgenic mice expressing an immature isoform of SNAP-25 (SNAP-25a), I propose to test the hypothesis that there is a developmental shift in the dominant form of LTD expressed in young mice that coincides with the shift from SNAP-25a to SNAP-25b expression. Finally, with two-photon laser scanning microscopy techniques, I will image vesicular release from distinct vesicle pools of Schaffer collateral presynaptic release sites, to test the role of biochemical cascades activated by NMDAR and mGluRIIs in induction of presynaptic LTD. Through identifying the mechanisms of interaction between activated NMDARs and mGluRIIs, and SNAP-25, I hope to further understanding of how long-term changes in transmitter release contribute to memory, and uncover mechanisms to ameliorate diseases such as Alzheimer's and epilepsy, where synaptic plasticity is altered.